Summary of Work: Methacrylonitrile (MAN) is a widely used aliphatic nitrile which is structurally similar to the known rat carcinogen, and suspected human carcinogen, acrylonitrile (AN). There is evidence that AN and MAN are metabolized via the cytochrome P450 enzymes. We recently identified 2 biliary conjugates originating from the interaction of MAN and its epoxide with glutathione. Mercapturic acids formed via the degradation of the 2 conjugates were also identified in rat and mouse urine. Additionally, a significant portion of MAN was eliminated in the expired air as CO2 (formed via the epoxide pathway) and unchanged MAN. The objective of the present work is to determine if CYP2E1 is involved in MAN metabolism as it was suggested for AN. 2-14C-MAN was administered to CYP2E1 -/- or CYP2E1 +/+ mice by gavage at 12 mg/kg. While CYP2E1- null animals exhaled greater than 30% of the administered dose as unchanged MAN, wild-type animals exhaled 1-3% of the dose as such. Additionally, CYP3E1-null and wild animals exhaled approximately 30 and 10% of the dose as CO2, respectively. Urinary and fecal excretion of MAN-derived metabolites were relatively similar in both CYP2E1-null and wild-type animals; however, preliminary analysis showed significant qualitative differences in the ratio of various metabolites on MAN in the urine.